Target Information

Target General Infomation
Target ID
T97071
Former ID
TTDS00441
Target Name
Glutamate carboxypeptidase II
Gene Name
FOLH1
Synonyms
FGCP; Folate hydrolase 1; Folylpoly-gamma-glutamate carboxypeptidase; MGCP; Membrane glutamate carboxypeptidase; N-acetylated-alpha-linked acidic dipeptidase I; NAALADase I; PSM; PSMA; Prostate-specific membrane antigen; Pteroylpoly-gamma-glutamate carboxypeptidase; FOLH1
Target Type
Successful
Disease Brain injury [ICD10: S09.90]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Influenza virus [ICD10: J11.1]
Metastatic prostate cancer; Non-metastatic prostate cancer [ICD9: 140-229, 185; ICD10: C61]
Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Prostate cancer [ICD9: 185; ICD10: C61]
Prostate cancer diagnosis [ICD9: 140-229, 185; ICD10: C61]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Has both folate hydrolase and n-acetylated-alpha-linked- acidic dipeptidase (naaladase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission.
BioChemical Class
Peptidase
Target Validation
T97071
UniProt ID
Q04609
EC Number
EC 3.4.17.21
Sequence
MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKA
FLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYP
NKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYA
RTEDFFKLERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVK
SYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYY
DAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIG
TLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFAS
WDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKE
LKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKN
WETNKFSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDY
AVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIV
LRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVD
PSKAWGEVKRQIYVAAFTVQAAAETLSEVA
Structure
1Z8L; 2C6C; 2C6G; 2C6P; 2CIJ; 2JBJ; 2JBK; 2OOT; 2OR4; 2PVV; 2PVW; 2XEF; 2XEG; 2XEI; 2XEJ; 3BHX; 3BI0; 3BI1; 3BXM; 3D7D; 3D7F; 3D7G; 3D7H; 3IWW; 3RBU; 3SJE; 3SJF; 3SJG; 3SJX; 4JYW; 4JZ0; 4LQG; 4MCP; 4MCQ; 4MCR; 4MCS; 4NGM; 4NGN; 4NGP; 4NGQ; 4NGR; 4NGS; 4NGT; 4OC0; 4OC1; 4OC2; 4OC3; 4OC4; 4OC5; 1Z8L; 2C6C; 2C6G; 2C6P; 2CIJ; 2JBJ; 2JBK;2OOT; 2OR4; 2PVV; 2PVW; 2XEF; 2XEG; 2XEI; 2XEJ; 3BHX; 3BI0; 3BI1; 3BXM; 3D7D; 3D7F; 3D7G; 3D7H; 3IWW; 3RBU; 3SJE; 3SJF; 3SJG; 3SJX; 4JYW; 4JZ0; 4LQG; 4MCP; 4MCQ; 4MCR; 4MCS; 4NGM; 4NGN; 4NGP; 4NGQ; 4NGR; 4NGS; 4NGT; 4OC0; 4OC1; 4OC2; 4OC3; 4OC4; 4OC5
Drugs and Mode of Action
Drug(s) Capromab Drug Info Approved Prostate cancer diagnosis [1], [2], [3]
99mTc-MIP-1404 Drug Info Phase 2 Prostate cancer [4]
ATL101 Drug Info Phase 2 Influenza virus [5]
G-202 Drug Info Phase 2 Solid tumours [6]
J 591 Lu-177 Drug Info Phase 2 Metastatic prostate cancer; Non-metastatic prostate cancer [7]
MLN-591RL Drug Info Phase 2 Prostate cancer [8]
MLN-2704 Drug Info Phase 1/2 Prostate cancer [9]
99mTc-MIP-1405 Drug Info Phase 1 Prostate cancer [10]
Autologous T-cell therapy Drug Info Phase 1 Prostate cancer [11]
BAY-1075553 Drug Info Phase 1 Prostate cancer [12]
GPI-16072 Drug Info Phase 1 Neuropathic pain [13]
Iofolastat I-124 Drug Info Phase 1 Prostate cancer [14]
MT-112 Drug Info Phase 1 Solid tumours [15]
PSMA subunit vaccine Drug Info Phase 1 Prostate cancer [16]
PSMA-targeted tubulysin B conjugates Drug Info Phase 1 Prostate cancer [17]
PSMA-VRP Drug Info Phase 1 Prostate cancer [18]
IRX-4 Drug Info Preclinical Prostate cancer [19]
MDX-070 Drug Info Discontinued in Phase 2 Prostate cancer [20]
2-PMPA Drug Info Terminated Discovery agent [21]
Inhibitor 2-(2-carboxy-5-mercaptopentyl)benzoic acid Drug Info [22]
2-(2-carboxy-7-mercaptoheptyl)benzoic acid Drug Info [22]
2-(2-Hydroxycarbamoyl-ethyl)-pentanedioic acid Drug Info [23]
2-(2-Mercapto-ethyl)-pentanedioic acid Drug Info [24]
2-(2-Phosphonooxy-ethyl)-pentanedioic acid Drug Info [24]
2-(3-carbamoylbenzyl)-5-mercaptopentanoic acid Drug Info [22]
2-(3-carboxybenzyl)succinic acid Drug Info [22]
2-(3-cyanobenzyl)-5-mercaptopentanoic acid Drug Info [22]
2-(3-Hydroxycarbamoyl-propyl)-pentanedioic acid Drug Info [23]
2-(3-Mercapto-propyl)-pentanedioic acid Drug Info [24]
2-(3-Methylsulfanyl-propyl)-pentanedioic acid Drug Info [24]
2-(4-Mercapto-butyl)-pentanedioic acid Drug Info [24]
2-(5-Mercapto-pentyl)-pentanedioic acid Drug Info [24]
2-(phosphonomethyl)pentanedioic acid Drug Info [25]
2-benzyl-5-mercaptopentanoic acid Drug Info [22]
2-Hydroxycarbamoyl-pentanedioic acid Drug Info [23]
2-Hydroxycarbamoylmethyl-pentanedioic acid Drug Info [23]
2-Mercapto-pentanedioic acid Drug Info [24]
2-Mercaptomethyl-pentanedioic acid Drug Info [24]
2-Phosphonooxy-pentanedioic acid Drug Info [24]
2-PMPA Drug Info [26]
3-(1-carboxy-4-mercaptobutoxy)benzoic acid Drug Info [22]
3-(2-carbamoyl-5-mercaptopentyl)benzoic acid Drug Info [22]
3-(2-carboxy-3-mercaptopropyl)benzoic acid Drug Info [22]
3-(2-carboxy-3-phosphonopropyl)benzoic acid Drug Info [22]
3-(2-carboxy-4-mercaptobutyl)benzoic acid Drug Info [22]
3-(2-carboxy-5-mercaptopentyl)benzoic acid Drug Info [22]
3-(2-carboxy-6-mercaptohexyl)benzoic acid Drug Info [22]
3-[(1-carboxy-4-mercaptobutyl)thio]benzoic acid Drug Info [22]
4-(2-carboxy-5-mercaptopentyl)benzoic acid Drug Info [22]
5-Mercapto-pentanoic acid Drug Info [24]
compound 8d Drug Info [27]
G-202 Drug Info [28]
GPI-16072 Drug Info [29]
Iofolastat I-124 Drug Info [30]
MIP-1375 Drug Info [31]
PGI-02749 Drug Info [31]
QUISQUALATE Drug Info [32]
Modulator 99mTc-MIP-1340 Drug Info [31]
99mTc-MIP-1404 Drug Info [33]
99mTc-MIP-1405 Drug Info [33]
ATL101 Drug Info [34]
BAY-1075553 Drug Info [35]
CTT-54 Drug Info [31]
J 591 Lu-177 Drug Info [7]
MDX-1147 Drug Info [31]
PSMA-targeted tubulysin B conjugates Drug Info [36]
Immunomodulator (Immunostimulant) IRX-4 Drug Info [37]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Alanine, aspartate and glutamate metabolism
Metabolic pathways
Vitamin digestion and absorption
NetPath Pathway TCR Signaling Pathway
TNFalpha Signaling Pathway
Reactome Amino acid synthesis and interconversion (transamination)
WikiPathways One Carbon Metabolism
References
REF 1FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (BLA) 103608.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6878).
REF 3Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 4ClinicalTrials.gov (NCT01667536) A Phase 2 Diagnostic Imaging Study With 99mTc-MIP-1404 in Men With High-Risk Prostate Cancer Scheduled for Radical Prostatectomy (RP) and Extended Pelvic Lymph Node Dissection (EPLND) Compared to Histopathology. U.S. National Institutes of Health.
REF 5Clinical pipeline report, company report or official report of Atlab pharma.
REF 6ClinicalTrials.gov (NCT01777594) Study of G-202 as Second-Line Therapy Following Sorafenib in Hepatocellular Carcinoma. U.S. National Institutes of Health.
REF 7Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res. 2013 Sep 15;19(18):5182-91.
REF 8ClinicalTrials.gov (NCT00195039) Treatment With Radiolabeled Monoclonal Antibody HuJ591-GS (177Lu-J591) in Patients With Metastatic Prostate Cancer. U.S. National Institutes of Health.
REF 9ClinicalTrials.gov (NCT00070837) MLN2704 in Subjects With Metastatic Androgen-Independent Prostate Cancer. U.S. National Institutes of Health.
REF 10ClinicalTrials.gov (NCT01261754) A Study of 99mTc-MIP-1404 and 99mTc-MIP-1405 in Patients With Metastatic Prostate Adenocarcinoma and Healthy Volunteers. U.S. National Institutes of Health.
REF 11Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunology. 2014 May 16;3(5):e16. doi: 10.1038/cti.2014.7. eCollection 2014.
REF 12Phase I Study: BAY 1075553 PET/CT in Staging and Re - Staging of Prostate Cancer Patients - Comparison with 18F-Choline PET/CT. World Molecular Imaging Society. September 20, 2013
REF 13Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis. Expert Opin Emerg Drugs. 2007 May;12(2):229-52.
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026421)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031326)
REF 16Clinical pipeline report, company report or official report of Alphavax.
REF 17J Clin Oncol 33, 2015 (suppl; abstr e13527)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012200)
REF 19Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026363)
REF 20Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015769)
REF 21Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009714)
REF 22J Med Chem. 2006 May 18;49(10):2876-85.Structural optimization of thiol-based inhibitors of glutamate carboxypeptidase II by modification of the P1' side chain.
REF 23Bioorg Med Chem Lett. 2003 Jul 7;13(13):2097-100.Synthesis and biological evaluation of hydroxamate-Based inhibitors of glutamate carboxypeptidase II.
REF 24J Med Chem. 2003 May 8;46(10):1989-96.Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor.
REF 25Bioorg Med Chem. 2008 Feb 15;16(4):1648-57. Epub 2007 Nov 17.Design and synthesis of a siderophore conjugate as a potent PSMA inhibitor and potential diagnostic agent for prostate cancer.
REF 26Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med. 1999 Dec;5(12):1396-402.
REF 27Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents. J Med Chem. 2004 Mar 25;47(7):1729-38.
REF 28National Cancer Institute Drug Dictionary (drug id 666090).
REF 29Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
REF 30123I-MIP-1072, a small-molecule inhibitor of prostate-specific membrane antigen, is effective at monitoring tumor response to taxane therapy. J Nucl Med. 2011 Jul;52(7):1087-93.
REF 31(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1606).
REF 32J Med Chem. 2007 Jul 12;50(14):3267-73. Epub 2007 Jun 14.Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II.
REF 3399mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med. 2013 Aug;54(8):1369-76.
REF 34Clinical pipeline report, company report or official report of Atlab pharma.
REF 35Preclinical evaluation of BAY 1075553, a novel (18)F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer. Eur J Nucl Med Mol Imaging. 2014 Jan;41(1):89-101.
REF 36Prostate-specific membrane antigen targeted imaging and therapy of prostate cancer using a PSMA inhibitor as a homing ligand. Mol Pharm. 2009 May-Jun;6(3):780-9.
REF 37Irx4 identifies a chamber-specific cell population that contributes to ventricular myocardium development. Dev Dyn. 2014 Mar;243(3):381-92.

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